Oral dosage form comprising an antimisuse system

ABSTRACT

An oral solid dosage form containing one or several active principle(s) having analgesic properties, the composition of said dosage form being such that it prevents the misuse of said dosage form through the liquid extraction of the active principle(s) contained therein, using commonly available solvents. Said oral solid dosage form containing at least one salt of at least one analgesic active principle, and an anti-misuse system comprising at least one quenching agent, said quenching agent being suitable for inducing complexation of said analgesic active principle salt when the analgesic active principle salt is improperly extracted, notably by a drug abuser, in vitro in solution from said oral solid dosage form.

FIELD OF THE INVENTION

The present invention relates to an oral solid dosage forms containingone or several active principle(s) having analgesic properties, thecomposition of said dosage form being such that it prevents theintentional or unintentional misuse of said dosage form through theliquid extraction of the active principle(s) contained therein, usingcommonly available solvents.

More specifically, the analgesic active principle (AAP) is present inthe oral solid dosage form is a pharmaceutically acceptable salt. In thepresent disclosure, the mention analgesic active principle means apharmaceutically acceptable salt of analgesic active principle.

BACKGROUND OF THE INVENTION

Analgesics, and more particularly opioid or morphine derivatives, areoften misused. Such misuse can be intentional or unintentionalconsumption of a solid oral drug containing an analgesic activeprinciple, for a purpose other than that which is officially approved bythe competent health authorities. This is a very complex and difficultproblem to solve. The reason is that drug abuses and unfortunately noweven teenagers have found way to recover the drug from tablets quiteeasily.

For example, today, teenagers prepare for parties on Saturday, acocktail of vodka with Oxycodon that they extract easily from tablets,with water or alcohol. The process consists in crushing the tablet andpouring the powder into a glass of vodka or water and then, to wait longenough to extract almost completely all the morphines derivative. Theyuse to do the preparation of the drug before they take it. This practiceis widespread in US but also in Europe. This is becoming a real socialconcern addressed by social agencies but also by the Food and DrugAdministration in US and European Agencies, who wish that dosage formspreventing misuse be developed.

There are other ways to misuse the type of opioid such as extracting thedrug as described above and make an intra-venous injection or dry thedrug in order to obtain a powder which can be inhaled.

There is a prior art describing different solution to avoid the misusageof opioids contained into a delivery systems.

Our understanding is that patent application US-A-2003/0224051 describesosmotic delivery dosage forms for the modified release of oxycodone. Thedosage form comprises an oxycodone core or acceptable salts thereof, asemi-permeable membrane at least partially surrounding the core, an exitorifice through the membrane allowing the release of oxycodone. Thistype of tablet allows an easy extraction by water for example after 12hours or more and consequently does not provide i.a. a satisfactorysolution against misuse.

Another way to avoid misuse of an opioid is to combine the opioid withits antagonist such as naltrexone. Our understanding is that patentapplication WO-A-03/013479 patent describes an oral dosage formcomprising a therapeutically effective amount of an opioid analgesic; anopioid antagonist (naltrexone); and a bittering agent. When the drugabuser crushes the tablet, the opioid and its antagonist are releasedand the opioid effect is neutralised.

This system does not prevent i.a extraction by water because, withoutcrushing, the opioid can be extracted, contrary to naltrexone.

Our understanding is that published European patent applicationEP-A-1293209 describes a solid oral pharmaceutical dosage form withreduced potential for drug abuse. The oral dosage form of the inventionis a sustained release dosage form based on an ion exchange resin whichcontains an opioid derivative. However, this dosage form does notprevent solvent extraction with an extraction time longer than thenormal release time of the drug. If said oral dosage form is left in aglass of water during 24 hours, most of the drug will be extracted.

As can be seen from the foregoing presentation of the prior art,different solutions are provided to prevent misuse of pharmaceuticalopioids in modified release solid dosage forms.

However, our understanding is that none of the solutions can preventi.a. the extraction by water, alcohol or any other type of drinkablesolvent.

OBJECTIVES OF THE INVENTION

In these circumstances, one of the main objects of the instant inventionis to fill in the prior art.

Thus, according to one aspect of the invention it is an object of theinvention to provide a new solid oral analgesic medicine/dosage form,allowing for the prevention of oral misuse after liquid extraction suchas a “long” liquid extraction of the analgesic active principle, in oneaspect without resorting to antagonists of the analgesic activeprinciple.

By “long liquid extraction”, it is meant that the liquid extraction isplanned by the drug abuser to last longer than 10 minutes.

According to further aspects of the invention, it is an objective of theinvention to provide a solid oral dosage form containing an analgesicactive principle, said dosage form having the following features:

Under normal prescribed condition of administration, the dosage formshould have the desired therapeutic effect, for example during 12 hoursor 24 hours;

Under any attempt of improper extraction of the analgesic by a misuser,the oral dosage form will not be able to provide fast absorption of theanalgesic into the blood circulation. Another objective of the inventionis to provide a new solid oral dosage form that prevents misuse by along liquid extraction as well as a brief liquid extraction and/or bycrushing.

Another objective of the invention is to provide a new solid oralanalgesic dosage form:

which can be administered easily to patients having difficulties toswallow large tablets, among which infants, children and the elderly;

which permits the association of several analgesic active principles, oreven other

nonanalgesic active principles, in a single dosage form, even when saidactive principles are not compatible with one another and/or when saidactive principles have distinct release kinetics;

which permits the provision of an oral pharmaceutical dosage form ofanalgesic active principle, or even other non-analgesic activeprinciples, which is administered once a day or several times a day, itbeing possible to adjust easily and independently the release rate andthe release time of said active principles.

A further object of the invention is to provide an oral pharmaceuticaldosage form of analgesic active principle, the in vitro dissolutionprofile of which is independent from the dose of analgesic activeprinciple.

Another object of the invention is to provide an oral pharmaceuticaldosage form of analgesic active principle, which can be administerede.g. once a day and which limits the risks of tissue damage due to localover-concentration of said active principle.

Still a further object of the invention is to provide an oralpharmaceutical dosage form of analgesic active principle which can beformulated into different galenical forms, such as tablets, powders,sachets, capsules and the like.

It is an object of the invention to provide a new solid oral drug thatprevents misuse while not compromising the treatment of a patient whoconforms to a regular therapy, in particular as regards this patient'sneeds in terms of dose of active principle.

Yet another objective of the invention is to provide a new solid oraldrug that prevents misuse, which is easily prepared and the preparationprocess of which does not unduly increase its manufacturing cost.

SUMMARY OF THE INVENTION

To achieve these objectives, it is to the inventor's credit to havediscovered means suitable to quench an analgesic active principle suchas an opioid when it is extracted from the dosage form for misusepurpose.

According to one aspect of the invention the dosage form has thefollowing features:

Under normal prescribed condition of administration, the dosage form hasthe desired therapeutic effect for example during 12 hours or 24 hours;

Under any attempt to extract the analgesic, with or without crushing,the analgesic is quenched in vitro by a safe and even generallyrecognized as safe substance (GRASS) in order to avoid its fastabsorption into the blood circulation and hence neutralize the fastaction of the drug;

The quenching agent forms a complex which is poorly soluble in water atany physiological pH from the stomach to the colon.

According to this aspect the invention provides a solid oral dosage formthat contains at least one quenching agent, this quenching agent beingsuitable for inducing complexation of the analgesic active principlewhen the analgesic salt is released in solution from the solid oraldosage form.

Within the meaning of this invention a “quenching agent” is an agentthat is present in the dosage form in a free form, i.e. in anon-complexed form, “non-complexed” meaning that no complex or chemicalinteraction of the quenching agent with the analgesic active principleexists within the dosage form. Only when the analgesic active agent andthe quenching agent are combined in a solvent, e.g. in case of anillicit extraction attempt, the quenching agent is suitable for inducingcomplexation or chemical interaction with the analgesic active principlein a common solvent as described herein. The quenching agent isconsidered to be “suitable to induce complexation” of the analgesicactive principle within the meaning of the present invention, when thequenching agent is suitable to induce said complexation (of theanalgesic active principle) in at least one common solvent selected fromthe group of water and aqueous solvent systems, such as water-ethanolmixtures, alcohol, alcoholic beverages, sodas, vinegar, and/or hydrogenperoxide, and mixtures thereof. Advantageously, the quenching agent issuitable to induce said complexation (of the analgesic active principlesalt) in more than one of these common solvents.

A further aspect of the invention is to provide a solid oral dosage formwherein the quenching agent cannot be removed from the system.

In other words, according to one aspect, the invention relates to anoral solid dosage form containing at least one salt of at least oneanalgesic active principle, and an anti-misuse system comprising atleast one quenching agent, said quenching agent being suitable forinducing complexation of said analgesic active principle salt when theanalgesic active principle salt is improperly extracted, notably by adrug abuser, in vitro in solution from said oral solid dosage form.

This solution was not self evident as it was necessary to define anefficient but a safe and generally recognized as safe substancequenching additive in the case where the drug abuser intends to extractthe drug. At the same time, the system should permit to release the drugin the body following the targeted pharmacokinetic profile. In otherwords, the desired pharmacological effect of the analgesic activeprinciple is not impaired by the quenching agent when the dosage form isnot misused. This new system will be called hereafter “Trigger Lock”system.

The invention provides a solid dosage form comprising an encapsulatedanalgesic active principle in a salt form and at least one quenchingagent such as e.g. an encapsulated quenching agent. In case of anencapsulated quenching agent said quenching agent is released at suchspeed that it can complex the analgesic active agent principle when itis itself released by extraction from the oral solid dosage form. Thequenching takes place when the quenching agent and the analgesic (e.g.for example the opioid) have been extracted in vitro by the solvent,forming a complex poorly soluble in the stomach medium. Thus, theconcentration of analgesic active principle remaining in solution is lowafter extraction, i.e. the amount of active principle remaining insolution is insufficient to provide the effects desired by the drugabuser.

Alternatively, the quenching agent can be an ion exchange resin, inwhich case the analgesic active principle does not form a complex withthe ion exchange resin when properly used. For instance, the quenchingagent can be a salt of an anionic exchange resin, the cation of which isH⁺, a metallic cation and/or NH4⁺. More precisely, according to thisaspect of the invention said ion exchange resin is comprised in a firstphase separate from a second phase, said second phase comprising saidanalgesic active principle.

According to one aspect the dosage form comprises microparticles ofanalgesic active principle and microparticles of quenching agent such asmicroparticles of ion exchange resin, said microparticles have the samesize distribution, the same density and are not sievable, i.e. noteasily separable.

These last characteristics of the Trigger Lock system ensure thatingestion of the complex does not lead to any fast regeneration and/orfast extraction of the analgesic active principle once ingested by thedrug abuser. Thus, the massive absorption of the analgesic, as desiredby the drug abuser, and the consequent massive blood concentration ofanalgesic, is avoided.

According to another aspect of the invention, the analgesic activeprinciple and the quenching agent are both in a modified release form.For example both the analgesic and the quenching agent could be releasedaccording to a sustained release kinetics. Thus, it is impossible, or atleast very difficult, to extract separately in vitro the analgesicactive principle and the quencher. In other words, the analgesic activeprinciple and quenching agent are necessarily extracted together andthus form a poorly soluble complex.

When the dosage form according to the instant invention is administeredorally in accordance with the prescriptions of the health authorities,said dosage form releases slowly both the analgesic active principle andthe quenching agent in the gastric fluids where they are both diluted,so that no complexation occurs. Then, the analgesic active principle canbe correctly bio-absorbed.

According to one aspect of the invention the dosage forms contain aplurality of microparticles.

It is also the inventors' credit to have designed a microparticulatesystem comprises a first microparticles population with the drug and asecond microparticles population with the quenching agent. Bothmicroparticles populations comprise a plurality of microparticles suchas more than 1,000 microparticles. This is believed to permit a fastdispersion of all the microparticles, thereby avoiding interaction ofthe quenching agent and the analgesic active principle in the body.

Without this being limiting, it is preferred according to the inventionthat the coated microparticles of PA have a mean diameter smaller thanor equal to 1000 μm, preferably comprising between 50 and 800 μm and,still preferably, comprising between 100 and 600 μm, and still betterbetween 100 and 300 μm.

According to one aspect of the invention it is also one element of theinvention to propose a delayed release for the quencher in order to haveenough time in the body to disperse the microparticles before thequencher neutralizes the analgesic active principle.

According to a further aspect of the invention, after administration ofthe dosage form according to the prescriptions of the healthauthorities, the analgesic is slowly released but the release of thequencher starts only after a lag time of typically 0.25 to 3 hours.During this lag time, the microparticles of analgesic and themicroparticles containing the quencher are broadly dispersed in thegastro-intestinal tract and the quencher can no longer neutralize theanalgesic.

Such a modified release of the quencher in the stomach, optionally aftera modified lag time is conveniently obtained by coating themicroparticles containing the quenching agent with a film coating, thecomposition of which is detailed hereinbelow.

According to an even further aspect of the invention themicroparticulate dosage forms are less easy to crush or to chew.

Preferably, the complex of the quenching agent and the analgesic ispoorly soluble in common solvents such as a water-ethanol mixture. Inother words, the concentration of analgesic active principle remainingin solution is low, i.e. the amount of analgesic active principle insolution is not sufficient to produce the effect desired by the drugabuser.

Preferably, the novel oral solid dosage form of the instant inventiondoes not contain antagonists of the analgesic active principle.

DETAILED DESCRIPTION OF THE INVENTION

The concept at the root of the invention is to include within a solidoral dosage form a quenching agent (quencher), namely a salt. This saltcomprises an ion which has a polarity opposite to that of the analgesicactive principle in solution. Preferably it is an organic ion such as anion exchange resin. It can also be a metallic ion.

When in solution, said ion replaces the initial counter-ion of theanalgesic active principle, leading to a substantially insolublecomplex. As a consequence, the analgesic active principle is no longerfree in solution. By “no longer free in solution” or “low concentration”is meant that the concentration of analgesic active principle remainingin solution is below the concentration desired by the drug abuser, or itis not sufficient to produce the desired effect by the drug abuser.

On the contrary, when the oral dosage form is administered according tothe regimen prescribed by the health authorities, the dilution of thequenching agents in the gastrointestinal tract fluids is sufficient toprevent the reaction of the quenching agent with the analgesic activeprinciple. Thus the therapeutic effect of the analgesic active principleis met.

Preferably, the active principles considered in the instant disclosureare analgesic active principles. Non-analgesic active principles canalso be included. In this specification, the mention of “an activeprinciple” or “the active principle” includes both the singular and theplural, and the mixture of different active principles.

The same convention applies to the mention of “a quenching agent” or“the quenching agent”. Both include the singular, the plural andmixtures of different quenching agents.

By “oral dosage form” is meant in this disclosure any dosage formwherein the active principle is comprised in tablets (monolithic dosageform) or in microparticles (multimicroparticulate dosage form). Thesedosage forms can be immediate release dosage forms or modified releasedosage forms. In the latter case, the tablet or the microparticle corecontaining the active principle can be coated with a polymer coatingthat controls the release rate of the active principle after oraladministration.

By “immediate release dosage form” is meant the release by a dosage formof the major part of the active principle dose in a short time, forinstance, 70% of the active principle are released in 1 hour, preferablyin 30 min., at any pH between 1.4 and 6.8, during an in vitrodissolution test.

By “modified release dosage form” is meant any dosage form wherein atleast a fraction of the active principle is released at a lower ratethan in an immediate release dosage form. This fraction can be comprisedbetween 1 and 100%, preferably, between 10 and 100%, and even morepreferably between 30 and 100%. A modified release dosage form cancomprise an immediate release phase and a sustained or delayed releasephase. Modified release dosage forms are well known in the art, see forinstance Remington: The science and practice of pharmacy, 19ème edition,Mack publishing Co. Pennsylvania, USA. Modified release comprises,notably, sustained release, delayed release, and pulsed release.

By “long liquid extraction”, it is meant that the liquid extraction isplanned by the drug abuser to last longer than 10 minutes.

By “household solvent” or “common solvent”, it is meant a liquid thatcan usually be found in a household and that can be used as anextraction solvent. For instance, it designates water and aqueoussolvent systems such as water-ethanol mixtures, alcohol, alcoholicbeverages, sodas, vinegar, and/or hydrogen peroxide, and mixturesthereof. Water-ethanol mixtures are encompassed as well.

Other definitions are given in the instant disclosure.

The quenching agents used to trap the analgesic active principle areinnocuous to the regular user. These quenching agents arepharmacologically inert, approved by the Pharmacopoeia and healthauthorities in charge of market approval of drugs. The quenching agentis selected so that, during an attempt to extract the active principlein an aqueous solution or an alcoholic aqueous solution, said quenchingagent forms a low solubility complex with the active principle insolution.

Preferably, the quenching agent comprises a salt, said salt containingions which form a complex with said analgesic active principle insolution. Said ions are preferably organic ions that have a polarityopposite to that of the analgesic active principle salt in solution.When the analgesic active principle salt is in the form of an anion insolution, the quenching agent comprises an organic cation, a metalliccation or a mixture thereof. Similarly, when the analgesic activeprinciple salt is in the form of a cation in solution, the quenchingagent comprises an organic anion.

For example, the following salts containing an organic anion can belisted:

-   -   organic anionic salts, such as sodium dodecyl sulfate or sodium        docusate;    -   anionic polymers, such as (meth)acrylic copolymers (for instance        Eudragit® S et L), crosslinked acrylic polyacids (for instance,        Carbopol), cellulose carboxymethycellulose and its derivates,        crosslinked carboxymethylcellulose and its derivates and other        polysaccharides (for instance, alginate, xanthane or arabic        gum), alginate (sulfonate)propylene glycol;    -   mono- or polyvalent salts, such as glucuronates, citrates,        acetates, carbonates, gluconates, succinates, phosphates,        glycerophosphates, lactates, trisilicates, fumarates, adipates,        benzoates, salicylates, tartrates, sulfonamides, acesulfames;    -   saponified fatty acids, such as the salts of acetic acid,        succinic acid, citric acid, stearic acid, palmitic acid, and        self emulsifying glyceryl mono-oleates;    -   polyamino acid, proteins or peptides, such as albumins, caseins,        globulins and enzymes;    -   and mixtures thereof.

In another embodiment, said ion having a polarity opposite to that ofthe analgesic active principle salt in solution, is a metallic cation,an organic cation, or a mixture thereof. For example, the followingsalts containing an organic cation or a metallic cation can be listed:

-   -   metallic cationic salts for example of Ca, Fe, Mg, Zn, in the        form of acesulfames, acetates, adipates, benzoates, carbonates,        chlorides, citrates, fluorides, fumarates, gluconates,        glucuronates, glycerophosphates, hydroxides, iodates, iodides,        lactates, oxides, phosphates, trisilicates, phosphates,        salicylates, succinates, sulfonamides, tartrates salts;    -   organic cationic salts, such as quaternary ammonium salts, in        particular trimethyl tetradecyl ammonium bromide or benzethonium        chloride;    -   cationic polymers, such as chitosan and (meth)acrylic copolymers        (for instance, Eudragit® RS, RL ou E);    -   polyamino acid, proteins or peptides;    -   and mixtures thereof.

The quenching agent can be an anionic exchange resin, in which case theanalgesic active principle does not form a complex with the ion exchangeresin. For instance, the quenching agent can be a salt of an anionicexchange resin, the cation of which is H⁺, a metallic cation and/or NH₄⁺. More precisely, said ion exchange resin is comprised in a first phaseseparate from a second phase, said second phase comprising saidanalgesic active principle.

The quenching agent Q can be an ion exchange resin, preferably a strongacid cation exchange resin where the AP is cationic, or a strong alcalianion exchange resin where the AP is anionic. Preferably, such an ionexchange resin is contained in a first phase distinct from a secondphase, said second phase containing the AP.

In an embodiment of the invention, the quenching agent is a strong acidcation exchange resin, derived for example from a sulphonated copolymerof styrene and divinylbenzene, such as Amberlite® IRP69, Amberlite®IR69F, Amberlite® 200, Amberlite® 200C, from Rohm & Haas, or Dowex® 88,from Dow, and the like.

In a further embodiment of the invention, the quenching agent is astrong alcan anion exchange resin, derived for example from copolymersof styrene and divinylbenzene with quaternary ammonium functionality,such as Duolite® AP143, Amberlite® IRA958, Amberlite® IRP67, from Rohm &Hass, or Dowex® 22, from Dow.

According to one embodiment the quenching agent is an ion exchange resinand the quenching agent is present in a first phase separate from atleast a second phase, said at least second phase comprising the PA salt.For instance, the first phase comprises microparticles comprising thequenching agent, separate from the second phase comprisingmicroparticles comprising the PA salt. The microparticles comprising thePA salt and microparticles comprising the quenching agent may be in sucha form where they have similar size distributions, similar densities andare not sievable.

According to one embodiment the quenching agent is an ion exchange resinand the quenching agent is present in a first phase separate from atleast a second phase, said at least second phase comprising the PA salt.For instance, the first phase comprises microparticles comprising thequenching agent, separate from the second phase comprisingmicroparticles comprising the PA salt. The microparticles comprising thePA salt and microparticles comprising the quenching agent may be in sucha form where they have the same size distribution, the same density andare not sievable.

In one embodiment of the invention, the quenching agent Q is chosen fromthe group consisting of:

anionic organic salts, such as sodium dodecyl sulfate or sodiumdocusate;

cationic organic salts, such as quaternary ammonium salts, in particulartrimethyl tetradecyl ammonium bromide or benzethonium chloride;

strong acid cation exchange resins, of strong alcali anion exchangeresins, depending on the AP polarity.

In another embodiment of the invention, the quenching agent Q is chosenfrom the group consisting of:

strong acid cation exchange resins, such as Amberlite® IRP69, Amberlite®IR69F, Amberlite® 200, Amberlite® 200C, from Rohm & Haas, or Dowex® 88,from Dow, and the like, and mixtures thereof, where the AP is cationic;

strong alcali anion exchange resins, such as Duolite® AP143, Amberlite®IRA958, Amberlite® IRP67, from Rohm & Hass, or Dowex® 22, from Dow, andmixtures thereof, where the AP is anionic.

The amount of quenching agent is adapted by the skilled man in the art,by computing the stoechiometric amount in terms of ionic charge,necessary to trap all or part of the dose of active principle containedin the dosage form. The amount must be at least sufficient to complex—incase of an illicit extraction attempt—the active principle to such anextent that the abuser does not achieve the desired high with theremaining active principle in solution. Preferably the amount is atleast sufficient to complex all of the contained active agent PA in thedosage form.

The quenching agent is selected in view of the chemical properties ofthe active principle it aims, in particular its ionic form in solution.

For the liquid extraction of the analgesic active principle, the dosageform containing the active principle is generally placed into anextraction solvent, such as a household liquid (water, organic solvents,sodas, alcoholic beverages) for a time period longer than 10 minutes.

Preferably, the dosage form according to the invention does not containan active principle that is an antagonist to the analgesic activeprinciple, particularly in the case of an opioid agonist.

Preferably, the dosage form according to the invention comprisesmodified release units of said analgesic active principle and modifiedrelease units of said quenching agent. For instance, said modifiedrelease units comprise microparticles selected from the groupcomprising: sustained release microparticles, delayed releasemicroparticles, pulsed release microparticles, and mixtures thereof.

A preferred embodiment is a multimicroparticulate dosage form. It ispreferred that, when the dosage form comprises microparticles ofanalgesic active principle and microparticles of quenching agent, saidmicroparticles have the same size distribution, the same density and arenot sievable.

Said dosage form can also be a monolithic dosage form.

According to a preferred embodiment, the quencher contained in the oralsolid dosage form of the invention is released following a modifiedrelease kinetic. Preferably, the quencher is contained in film coatedmicroparticles, and most preferably, in microparticles coated with thesame film coating as that used to coat the microparticles containing theanalgesic active principle.

According to a preferred embodiment, the dosage form comprises a furtherantimisuse agent. Said further antimisuse agent aims at preventing drugabuse by injection, after a possible crushing and liquid extraction. Inan additional embodiment, said further antimisuse agents are provided toprevent drug abuse by inhalation, after a possible crushing and liquidextraction. Therefor, said further antimisuse agent comprises ananti-crushing agent (a) and/or a viscosity agent (b).

Preferably, said anti-crushing agent (a) comprises:

a protective over-coating on said microparticles, said over-coatinghaving at least one of the following features:

-   -   viscoelastic properties, to absorb the energy dissipated during        crushing;    -   a low cohesivity, to favor breaking of the over-coating rather        than breaking of the microparticles during crushing;    -   a low surface energy, to favor gliding of the microparticles one        on the other during crushing;    -   an ability to form a paste under high shear,

and/or free additives, i.e. additives that are not contained in norborne over microparticles, said additives being suitable to impair, oreven to prevent completely, the crushing of the pharmaceutical dosageform containing said analgesic active principle.

In the case where an over-coating is provided to protect the dosageform, such as microparticles, the over-coating is prepared so that anon-immediate release of the analgesic active principle takes place evenafter the dosage form has been crushed.

More precisely, the over-coating of the dosage form comprises:

(i) at least one film forming polymer insuring the cohesion of theover-coating;

and at least one of the following compounds:

-   -   (ii) a lubricant/lump agent    -   (iii) a viscoelastic compound    -   (iv) a plasticizer.

In practice, said film-forming polymer (i) is selected from the groupcomprising cellulose derivatives, acrylic polymers and mixtures thereof.

Said lubricant/lump agent (ii) is selected from the group comprising:

stearic acid, stearates, preferably calcium stearate, zinc stearate ormagnesium stearate,

magnesium oxide,

poloxamers,

sodium benzoate,

anionic, cationic or non-ionic surfactants,

starch, preferably corn starch,

talc,

colloïdal silica,

waxes, preferably hydrogenated vegetable oils, and more preferably:cotton hydrogenated oils, soybean hydrogenated oils, palm hydrogenatedoils, glycerol behenate, castor hydrogenated oils, tristearines,tripalmitines, trimyristines, yellow wax, white wax, hard fat, dairyanhydrous fat, lanolins, glycerol palmitostearate, glycerol stearates,lauric acid macrogolglycerids, cetyl alcohols, polyglycryledi-isostearate, diethylene glycol monostearate, ethylene monostearate,omega-3 fatty acids, and mixtures thereof,

suppository fatty base, comprising glycerine, triglycerids, theobromaoils, cocoa butter, and mixtures thereof,

mixtures thereof.

Said viscoeslastic compound (iii) is selected from the group comprising:

poly-N-vinylamides,

gums,

fatty alcohols,

poly-N-vinyl-lactams,

polyvinyl alcohols,

polyoxiethylenes,

polyethylene glycols,

polydextroses,

hydrogenated mono-, di- and polysaccharides,

polyvinylpyrrolidones, these being preferred,

and mixtures thereof.

Said plasticizer (iv) is selected from the group comprising:

glycerol, glycerol esters, preferably acetylated glycerides,glycerylmonostearates, glyceryltriacetate, glyceryltributyrate,

phtalates, preferably: dibutylphthalate, diethylphthalate,dimethylphthalate, dioctylphthalate,

citrates, preferably: acetyltributylcitrate, acetyltriethylcitrate,tributylcitrate, triethylcitrate,

sebaçates, preferably: diethylsebaçate, dibutylsebaçate,

adipates,

azelates,

benzoates,

vegetable oils, preferably: cotton oils, soybean oils, palm oils, castoroils, and mixtures thereof,

fumarates, preferably: diethylfumarate,

malates, preferably: diethylmalate,

oxalates, preferably: diethyloxalate,

succinates; preferably: dibutylsuccinate,

butyrates,

cetyl alcohol esters,

triacetine,

malonates, preferably: diethylmalonate,

and mixtures thereof.

The additive possibly comprised in the anti-crushing agent (a) ispreferably selected from the group comprising: compression agents,and/or inert microbeads, and/or gums, and/or viscoelastic compound asdefined above.

The viscosity agents, intended to prevent misuse of the analgesic activeprinciple after a possible liquid extraction, aim at increasing theviscosity of the extracted liquid, so as to impair misuse, notably byinjection.

The viscosity agents are preferably located in microcapsules containingsaid viscosity agents, and/or on microcapsules containing the activeprinciple, and/or in a partial or total overcoating of said dosage form,and/or free from said dosage form.

Preferably, said viscosity agent is selected from the group comprising:

acrylic polyacids and derivatives thereof, and/or

polyoxyethylenes, and/or

polyvinyl alcohol, and/or

polyvinylpyrrolidones, and/or

gelatins

-   -   cellulose derivatives, for instance        hydroxypropylmethylcellulose, methylcellulose,        hydroxyethylcellulose, carboxymethylcellulose,        hydroxypropylcellulose, and/or

polysaccharides, preferably from the group comprising sodium alginate,pectins, guar, xanthanes, carraghenanes, gellanes, and/or

mixtures thereof.

The oral dosage form according to the invention presents at least one ofthe following remarkable features:

It cannot, or with difficulty, be transformed into a dry inhalable form;

It cannot, or with difficulty, be transformed into a liquid injectableform;

The extraction of the analgesic active principle by chewing is notefficient;

Moreover, the liquid extraction of the analgesic active principle leadsto the complexation of said active principle, thereby rendering ituseless by the oral route.

The dosage form according to the invention can comprise, in addition tomicro-units made of modified release microcapsules of analgesic activeprinciple, micro-units of analgesic active principle other thanmicrocapsules, among which immediate release micro-granules.Advantageously, said micro-granules are not coated and are of the sametype as those used to prepare microcapsules according to the invention.

Advantageously, said analgesic active principle is an opioid activeprinciple, preferably an opioid agonist, in the form of a salt.Preferably, said opioid active principle is selected from the groupcomprising: anileridine, acetorphine, acetylalphamethylfentanyl,acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine,alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol,alphamethylfentanyl, alpha-methylthiofentanyl, alphaprodine,anileridine, atropine, butorphanol, benzethidine, benzylmorphine,beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol,betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine,butyrate de dioxaphetyl, clonitazene, cyclazocine, cannabis,cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine,dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine,dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene,difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate,dipipanone, drotebanol, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,etoxeridine, fentanyl, furethidine, heroine, hydrocodone,hydromorphinol, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphane, lofentanil, levomethorphane, levomoramide,levophenacylmorphane, levorphanol, meptazinol, meperidine, metazocine,methadone, methyldesorphine, methyldihydro-morphine, methylphenidate,methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide,morpheridine, morphine, mppp, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine,norlevorphanol, normethadone, normorphine, norpipanone, opium,oxycodone, oxymorphone, papavereturn, phenadoxone, phenoperidine,promedol, properidine, propiram, propoxyphene para-fluorofentanyl,pepap, pentazocine, pethidine, phenampromide, phenazocine,phenomorphane, phenoperidine, pholcodine, piminodine, piritramide,proheptazine, propanolol, properidine, propiram, racemethorphane,racemoramide, racemorphane, remifentanil, sufentanil, thebacone,thebaine, thiofentanyl, tilidine, trimeperidine, tramodol,pharmacologically acceptable salts thereof and their mixtures.

The oral dosage forms according to the instant invention can comprise atleast one further active principle, distinct from an analgesic activeprinciple. This non-analgesic active principle is preferably selectedfrom the group comprising: anti-depressants amphetamines, anorectics,pain killers, antiepileptics, anitmigraines, antiparkinson agents,antitussives, anxiolytics, barbiturics, benzodiazepines, hypnotiqcs,laxatives, neuroleptics, psychostimulants, psychotropes, sedatives,stimulants, anti-inflammatory agents, the pharmacologically acceptablesalts thereof, and their mixtures.

As regards anti-inflammatory active principles, the following can belisted: ibuprofen, acetaminophen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozine, pramoprofen, muroprofen, trioxaprofen, suprofen,amineoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacine,sulindac, tolmetine, zomepirac, tiopinac, zidometacine, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam or isoxicam, the pharmacologically acceptable saltsthereof, and their mixtures.

The dosage form can be a modified release dosage form or a combinationof a modified release form and an immediate release form. The activeprinciple can be comprised into modified release microparticles andpossibly into immediate release microparticles.

The modified release multiparticulate form of the oral analgesic activeprinciple composition according to the invention, can be:

a reservoir type form

and/or a matricial type form.

“Reservoir type form”, is intended to denote, in the present disclosure,a form in which the volume of material containing the active principleis entirely coated by at least a film which controls the diffusionrelease speed of the active principle through the continuous film (ormembrane) which does not include the active principle. This releaseoccurs as a result of the contact of the system with the liquid of thegastro intestinal tract. The active principle containing material is,for example, the active principle in itself, a mixture of pharmaceuticaladditives or a mixture of pharmaceutical additives with the activeprinciple. The reservoir form comprises, for example, a plurality ofindividually coated microcapsules or a monolithic system such as coatedtablet(s), a tablet or any other pharmaceutical form containing aplurality of coated microcapsules.

“Matricial type form” is intended to denote, in the present disclosure,a form in which the analgesic active principle is dispersed in a solidcontinuous (polymeric) phase (the matrix) that controls the diffusionrelease speed of the active principle. Said matrix can or cannot beerodable. Said matrix e.g. consists of pharmaceutically acceptableadditives known by the man skilled in the art. The matricial type formincludes, for instance, a plurality of matricial micro-granules(matricial elements) containing the active principle. These matricialelements are non-coated or partially coated. The matricial type form canbe, e.g., also a monolithic system (matricial element), such as atablet(s) non-entirely coated by at least one continuous film, whichdoes not contain any reservoir form. So, the matricial type form can be,e.g. a tablet containing a plurality of active principle immediaterelease granules or active principle(s) sustained release granules, saidgranules being dispersed in a polymeric matrix.

In an embodiment of the invention, the dosage form comprises a pluralityof microparticles for the modified release of said analgesic activeprinciple, each microparticles individually comprising a core and acoating on said core. The core comprises at least one analgesic activeprinciple and the coating controls the modified release of said activeprinciple. Preferably, said microparticles have a mean diameter (involume) lower than or equal to 1,000 μm.

In a first embodiment of the dosage form according to the invention, themodified release form of the analgesic active principle is a sustainedrelease form with an in vitro release profile, such that 70% of theactive principle is released over a period of time of between 1 and 24hours, preferably 2 and 12 hours and even more preferably between 2 and8 hours.

Advantageously, the composition of the individual coating of themicroparticles or the matrix of the microparticles, according to thefirst embodiment, corresponds to one of the two following families A andB:

Family A

—A1—at least one film-forming polymer (P1) which is insoluble in thefluids of the tract, present in a proportion of 50 to 90%, preferably 50to 80%, by weight on a dry basis with respect to the total mass of thecoating composition and composed of at least one water-insolublecellulose derivative of cellulose,

—A2—at least one nitrogenous polymer (P2), present in a proportion of 2to 25%, preferably 5 to 15%, by weight on a dry basis with respect tothe total mass of the coating composition and composed of at least onepolyacrylamide and/or one poly-N-vinylamide and/or onepoly-N-vinyllactam,

—A3—at least one plasticizer, present in a proportion of 2 to 20%,preferably of 4 to 15%, by weight on a dry basis with respect to thetotal mass of the coating composition and composed of at least one ofthe following compounds: glycerol esters, phthalates, citrates,sebacates, esters of cetyl alcohol, castor oil, and salicylic acid;

—A4—at least one surface-active and/or lubricating agent, present in aproportion of 2 to 20%, preferably of 4 to 15%, by weight on a dry basiswith respect to the total mass of the coating composition and chosenfrom anionic surfactants, and/or from nonionic surfactants, and/or fromlubricating agents, it being possible for said agent to comprise justone or a mixture of products mentioned above.

Family A can be exemplified as follows:

—A1—ethylcellulose and/or cellulose acetate,

—A2—polyacrylamide and/or polyvinylpyrrolidone;

—A3—castor oil,

—A4—alkali metal or alkaline earth metal salts of fatty acids, stearicacid and/or oleic acid being preferred; polyoxyethylenated sorbitanesters and/or polyoxyethylenated castor oil derivatives; stearates,preferably calcium stearate, magnesium stearate, aluminium stearate orzinc stearate.

Family B

—B1—at least one film-forming polymer insoluble in the gastrointestinaltract fluids;

—B2—at least one water-soluble polymer;

—B3—at least one plasticizer;

—B4—optionally at least one surfactant/lubricant preferably comprisingat least an anionic surfactant and/or at least a non-ionic surfactant,

Family B can be exemplified as follows:

—B1—

-   -   water-insoluble cellulose derivatives, ethyl cellulose and/or        cellulose acetate being particularly preferred;    -   acrylic derivatives;    -   polyvinyl acetates;    -   and mixtures thereof;

—B2—

-   -   water-soluble cellulose derivatives;    -   polyacrylamides; poly-N-vinylamides;    -   poly-N-vinyllactams;    -   polyvinyl alcohols;    -   polyoxyethylenes;    -   polyvinylpyrrolidones (the latter being preferred); and mixtures        thereof;

—B3—

-   -   glycerol and its esters, preferably from the following subgroup:        acetylated glycerides, glycerol monostearate, glyceryl        triacetate and glycerol tributyrate;    -   phthalates, preferably from the following subgroup: dibutyl        phthalate, diethyl phthalate, dimethyl phthalate and dioctyl        phthalate;    -   citrates, preferably from the following subgroup: acetyltributyl        citrate, acetyltriethyl citrate, tributyl citrate and triethyl        citrate;    -   sebacates, preferably from the following subgroup: diethyl        sebacate and dibutyl sebacate;    -   adipates;    -   azelates;    -   benzoates;    -   vegetable oils;    -   fumarates, preferably diethyl fumarate;    -   malates, preferably diethyl malate;    -   oxalates, preferably diethyl oxalate;    -   succinates, preferably dibutyl succinate;    -   butyrates;    -   cetyl alcohol esters;    -   salicylic acid;    -   triacetin;    -   malonates, preferably diethyl malonate;    -   castor oil (this being particularly preferred);    -   and mixtures thereof;

—B4—

-   -   alkali metal or alkaline earth metal salts of fatty acids,        stearic and/or oleic acid being preferred;    -   polyethoxylated oils, preferably polyethoxylated hydrogenated        castor oil;    -   polyoxyethylene/polyoxypropylene copolymers;    -   polyethoxylated sorbitan esters;    -   polyethoxylated castor oil derivatives;    -   stearates, preferably calcium, magnesium, aluminium or zinc        stearate;    -   stearylfumarates, preferably sodium stearylfumarate;    -   glycerol behenate;    -   and mixtures thereof.

Preferably, the coating comprises a single layer, the weight of whichrepresents between 1 and 50%, preferably between 5 and 40%, by weight,of the total weight of said microparticles.

For further details, in particular qualitative and quantitative details,regarding at least some of the constituents of this coating composition,reference will be made, for example, to European patent EP-B-0 709 087or to PCT applications WO-A-2004/010983 and WO-A-2004/010984, thecontent of which is integrated into the present disclosure by way ofreference.

According to a second embodiment of the solid oral dosage form accordingto the invention, the modified release solid oral dosage form ofanalgesic is a sustained release form with an in vitro dissolutionbehaviour such that:

the release of analgesic is controlled by means of two distincttriggering mechanisms, one being based on a variation in pH and theother allowing the release of the active principle(s) after apredetermined period of residence in the stomach;

at constant pH 1.4, the dissolution profile comprises a lag phase ofless than or equal to 7 hours, preferably less than or equal to 5 hours,and even more preferably of between 0.25 and 5 hours;

and the change from pH 1.4 to pH 7.0 results in a release phase thatbegins without any lag time.

More preferably, the modified release solid oral dosage form accordingto this second embodiment has an in vitro dissolution behaviour,measured in an in vitro dissolution test, such that:

less than 20% of the analgesic is released after 2 h at pH 1.4;

at least 50% by weight of the analgesic is released after 16 h at pH1.4.

According to the second embodiment of the invention, the analgesicactive principle is released in vitro according to a double triggermechanism, from microparticles containing said active principle. Thecoating or the matrix for modified release of the active principlecomprises:

at least one hydrophilic polymer (I) carrying groups that are ionized atneutral pH,

at least one hydrophobic compound (II); the mean diameter of saidmicroparticles is less than 2000 μm, and preferably between 50 and 800μm, and even more preferably between 100 and 600 μm.

According to another advantageous characteristic, the composite materialI-II for the coating for modified release of the active principle withlow solubility is such that:

the II/I weight ratio is between 0.2 and 1.5, preferably between 0.5 and1.0,

and the hydrophobic compound II is selected from products that arecrystalline in the solid state and that have a melting point MpB≧40° C.,preferably MpB≧50° C., and even more preferably 40° C.≦MpB≦90° C.

According to a species of predilection, the hydrophilic polymer (I) ischosen from:

I.a copolymers of (meth)acrylic acid and of (meth)acrylic acid alkylester, and mixtures thereof;

I.b cellulose derivatives, preferably cellulose acetates, cellulosephthalates, cellulose succinates and mixtures thereof, and even morepreferably hydroxypropylmethylcellulose phthalates,hydroxypropylmethylcellulose acetates, hydroxypropylmethylcellulosesuccinates and mixtures thereof;

and mixtures thereof.

The polymers (I) that are even more preferred are copolymers of(meth)acrylic acid and of (meth)acrylic acid alkyl (e.g. C₁-C₆ alkyl)esters. These copolymers are, for example, of the type of those sold bythe company Rohm Pharma Polymers under the registered trade marksEUDRAGIT®, series L and S (such as, for example, EUDRAGIT® L100, S100,L30 D-55 and L100-55). These copolymers are anionic enteric copolymersthat are soluble in aqueous medium at pHs above those encountered in thestomach.

Still according to the embodiment of predilection, the compound (II) ischosen from the group of products below:

II.a plant waxes taken on their own or as mixtures with one another;

II.b hydrogenated plant oils taken on their own or as mixtures with oneanother;

II.c mono- and/or di- and/or triesters of glycerol and of at least onefatty acid;

II.d mixtures of monoesters, of diesters and of triesters of glyceroland of at least one fatty acid;

and mixtures thereof.

Even more preferably, the compound (II) is chosen from the group offollowing products:

hydrogenated cottonseed oil, hydrogenated soybean seed oil, hydrogenatedpalm oil, glyceryl behenate, hydrogenated castor oil, tristearin,tripalmitin, trimyristin, yellow wax, hard fat or fat that is useful assuppository bases, anhydrous dairy fats, lanolin, glycerylpalmitostearate, glyceryl stearate, lauryl macrogolglycerides, cetylalcohol, polyglyceryl diisostearate, diethylene glycol monostearate,ethylene glycol monostearate, omega-3 and any mixture thereof,

preferably from the subgroup of following products: hydrogenatedcottonseed oil, hydrogenated soybean seed oil, hydrogenated palm oil,glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin,trimyristin and any mixture thereof.

In practice, and without this being limiting, it is preferable for thecompound (II) to be chosen:

from the group of products sold under the following trade marks:Dynasan®, Cutina®, Hydrobase®, Dub®, Castorwax®, Croduret®, Compritol®,Sterotex®, Lubritab®, Apifil®, Akofine®, Softtisan®, Hydrocote®,Livopol®, Super Hartolan®, MGLA®, Corona®, Protalan®, Akosoft®, Akosol®,Cremao®, Massupol®, Novata®, Suppocire®, Wecobee®, Witepsol®, Lanolin®,Incromega®, Estaram®, Suppoweiss®, Gelucire®, Precirol®, Emulcire®,Plurol diisostéarique®, Geleol®, Hydrine® and Monthyle®, and mixturesthereof;

and also from the group of additives for which the codes are as follows:E 901, E 907, E 903 and mixtures thereof;

and, preferably, from the group of products sold under the followingtrade marks: Dynasan® P60, Dynasan® 114, Dynasan® 116, Dynasan® 118,Cutina® HR, Hydrobase® 66-68, Dub® HPH, Compritol® 888, Sterotex® NF,Sterotex® K, Lubritab® and mixtures thereof.

According to another advantageous characteristic of this embodiment, thecoating for modified release of the active principle is free of talc.

For further details regarding the preparation of these microparticlesaccording to this embodiment, in particular in their embodiment with aneutral core coated with at least one active layer comprising activeprinciple(s) and with at least one outer coating for modified release ofthe active principle(s), reference will be made to the content of PCTapplication WO-A-FR03/030878, the content of which is integrated intothe present disclosure by way of reference.

According to a third embodiment of the invention, the dosage formcomprises at least two different populations of microparticles. Eachpopulation of modified release micro-particles can correspond either tothe first embodiment, or the second embodiment as disclosed above.

According to a fourth embodiment of the invention, the dosage formcomprises an immediate release microparticles population and at leastone modified release microparticles population.

The above-mentioned coated microparticles may have different structures.According to a first structure, some of the microparticles comprise acore containing the active principle and a coating over the core, saidcoating allowing the modified release of the active principle.

According to a second structure, some of the microparticles comprise acore containing a neutral core and at least a layer containing theactive principle and coating the neutral core, said microparticlefurther containing a coating over the core, said coating allowing themodified release of the active principle.

Preferably, in the dosage form according to the invention, theantimisuse agent is located:

in microparticles containing said antimisuse agent, and/or

in a matrix containing said analgesic active principle, and/or

in a coating of microparticles containing said analgesic activeprinciple, and/or

in a partial or total over-coating of said dosage form, and/or

free from said dosage form.

As regards the microparticles containing the quenching agent, they canbe coated with a film coating, the composition of which is chosenamongst families A and B as disclosed above (first embodiment of thedosage form containing the analgesic active principle).

These microparticles containing the quenching agent release thequenching agent with an in vitro release profile such that, for example,70% of the quenching agent is released for a period of time between 1and 24 h, preferably 2 and 12 h, more preferably 2 and 8 h.

The microparticles containing the quenching agent release the quenchingagent can also be coated with a coating as disclosed for the secondembodiment mentioned above. The quenching agent is released, forexample, with an in vitro release profile with an in vitro dissolutionbehavior such that:

the release of the quenching agent is controlled by means of twodistinct triggering mechanisms, one being based on a variation in pH andthe other allowing the release of the active principle(s) after apredetermined period of residence in the stomach;

at constant pH 1.4, the dissolution profile comprises a lag phase ofless than or equal to 7 hours, preferably less than or equal to 5 hours,and even more preferably of between 0.25 and 5 hours;

and the change from pH 1.4 to pH 7.0 results in a release phase thatbegins without any lag time.

More preferably, the modified release solid oral dosage form accordingto this second embodiment has an in vitro dissolution behavior, measuredin an in vitro dissolution test, such that for example:

less than 20% of the quenching agent is released after 2 h at pH 1.4;

at least 50% by weight of the quenching agent is released after 16 h atpH 1.4.

Advantageously, these dosage forms, novel in their structure, theirpresentation and their composition, are presented in the form of atablet, a sachet of powder, a sachet of a powder for multidosesuspension to be reconstituted, a tablet or a gelatin capsule.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates example 2. It is a picture of the solutions obtainedas follows:

A: Solution A is oxycodone HCl at 5 g/L in water

B: Solution B is SDS at 5 g/L in water

A+B: Solution A and B mixed, a precipitate entrapping the oxycodone isformed

FIG. 2 illustrates the in vitro dissolution profile of microparticles ofexample 3 in a reference test (% AP dissolved v. time)

FIG. 3 shows a picture of the content of a capsule according to example4, by the naked eye (A) and with an optical microscope (B).

EXAMPLES Example 1 Oxycodone Misuse Resistive Capsule

Step 1:

600 g of Oxycodone HCl and 60 g of Klucel EF® (Hydroxypropylcellulose/Aqualon) are dissolved in 5000 g of water. The solution issprayed onto 300 g of neutral microspheres (Asahi-Kasei) in a GPCG1Glatt spray coater. 35 g of ethyl cellulose (Ethocel 20 Premium/Dow), 5g of Plasdone K29/32® (Povidone/ISP), 2.5 g of Cremophor RH 40(Macrogolglyceroli hydroxystearas/BASF) and 7.5 g of castor oil aredispersed in a 60% isopropanol and 40% acetone mixture. This solution issprayed onto 350 g of Oxycodone granules previously prepared.

Step 2:

550 g of sodium dodecylsulfate (SDS) and 50 g of Klucel EF®(Hydroxypropyl cellulose/Aqualon) are dispersed in 3000 g of ethanol.The solution is sprayed onto 250 g of neutral microspheres (Asahi-Kasei)in a GPCG1 Glatt spray coater. 30 g of HPMC (Hypromellose K15 MP/Dow),10 g of Plasdone K29/32® (Povidone/ISP), 2.5 g of Cremophor RH 40(Macrogolglyceroli hydroxystearas/BASF) and 7.5 g of castor oil aredispersed in a 60% isopropanol and 40% acetone mixture. This solution issprayed onto 450 g of SDS granules previously prepared.

Step 3:

146 mg of micro-particules obtained in step 1 are mixed with 105 mg ofmicro-particules obtained in step 2 and put in a size 1 gelatin hardcapsule.

If the capsule is broken and emptied in a glass of water a precipitatecontaining the Oxycodone is obtained.

Example 2 Quenching of Oxycodone Hydrochloride by Sodium Dodecylsulfatein Water

In example 2, two solutions were prepared. Solution A is Oxycodonehydrochloride at 5 g/L in tap water. Solution B is SDS (sodiumdodecylsufate) at 5 g/L in tap water.

Solution A is added to solution B. The resulting solution A+B is turbid.After a few minutes, a complex containing the oxycodone precipitates.This complex remains stable even if diluted in a larger amount of tapwater (more than 2 times).

Therefore, oxycodone cannot be misused, either by oral administration orby injection of a concentrated solution.

Example 3 Oxycodone Misuse Resistive Capsules

Step 1: Granule

1615 g oxycodone and 85 g Povidone (Plasdone® K29-32/ISP) were dispersedin 60:40 v/v water/ethanol. This solution was sprayed over 300 g ofcellulose spheres (Asahi-Kasei) in a fluid bed coater (Glatt GPCG1).

Step 2: Anti-Crushing Microparticles

315 g ethylcellulose (Ethocel 20 Premium/Dow), 81 g de povidone(Plasdone K29-32/ISP), 18 g de Macrogolglyceroli hydroxystearas(Cremophor RH40/BASF) and 36 g castor oil (Garbit Huilerie) aredissolved in 60:40 v/v acetone/isopropanol. This solution is sprayedover 450 g granules obtained from step 1.

The coating whose mass is 50 wt % of the total mass of the coatedmicroparticles, leads to the dissolution profile of FIG. 2. Thedissolution test is performed according to the reference dissolutiontest.

Example 4 Oxycodone Misuse Resistive Capsule

230 mg microparticles obtained from step 2 of Example 3, 100 mg ofcrushed and sieved Amberlite IR69F (sodium polystyrene sulfonate), 70 mgsieved Polyox WSR 303 Sentry (polyethylene oxyde), 3.8 mg magnesiumstearate and 1.9 mg d'Aerosil 200 (colloidal silica) are filled in asize 0 gelatin capsule.

This oxycodone capsule is protected against misuse.

As shown in FIG. 3A (naked eye) and 3B (optical microscope), APmicroparticles and viscosity agent microparticles cannot bedistinguished and cannot be sieved.

1. An oral solid dosage form containing at least one salt of at leastone analgesic active principle, and an anti-misuse system comprising atleast one quenching agent, said quenching agent being suitable forinducing complexation of said analgesic active principle salt when theanalgesic active principle salt is improperly extracted, notably by adrug abuser, in vitro in solution from said oral solid dosage form. 2.The dosage form according to claim 1, wherein the desiredpharmacological effect of the analgesic active principle is not impairedby the quenching agent when the dosage form is not misused.
 3. Thedosage form according to claim 1 or 2, wherein the concentration ofanalgesic active principle remaining in solution is low afterextraction.
 4. The dosage form according to any one of the precedingclaims, wherein said quenching agent comprises a salt, said saltcontaining ions which form a complex with said analgesic activeprinciple salt extracted in solution.
 5. The dosage form according toany one of the preceding claims, wherein said quenching agent comprisesa salt, said salt containing ions, preferably organic ions, having apolarity opposite to that of the analgesic active principle salt insolution, said ions forming a complex with said analgesic activeprinciple salt extracted in solution.
 6. The dosage form according toclaim 5, wherein said ion having a polarity opposite to that of theanalgesic active principle salt in solution, is an organic anion.
 7. Thedosage form according to any one of the preceding claims, wherein thequenching agent comprises a salt selected from the group comprising:organic anionic salts, such as sodium dodecyl sulfate or sodiumdocusate; anionic polymers, such as (meth)acrylic copolymers (forinstance Eudragit® S et L), crosslinked acrylic polyacids (for instance,Carbopol), cellulose carboxymethycellulose and its derivates,crosslinked carboxymethylcellulose and its derivates and otherpolysaccharides (for instance, alginate, xanthane or arabic gum),alginate (sulfonate)propylene glycol; mono- or polyvalent salts, such asglucuronates, citrates, acetates, carbonates, gluconates, succinates,phosphates, glycerophosphates, lactates, trisilicates, fumarates,adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;saponified fatty acids, such as the salts of acetic acid, succinic acid,citric acid, stearic acid, palmitic acid, and self emulsifying glycerylmono-oleates; polyamino acid, proteins or peptides, such as albumins,caseins, globulins and enzymes; and mixtures thereof.
 8. The dosage formaccording to any one of claims 1 to 5, wherein said ion having apolarity opposite to that of the analgesic active principle salt insolution, is a metallic cation, an organic cation, or a mixture thereof.9. The dosage form according to claim 8, wherein the quenching agentcomprises a salt selected from the group comprising: metallic cationicsalts for example of Ca, Fe, Mg, Zn, in the form of acesulfames,acetates, adipates, benzoates, carbonates, chlorides, citrates,fluorides, fumarates, gluconates, glucuronates, glycerophosphates,hydroxides, iodates, iodides, lactates, oxides, phosphates,trisilicates, phosphates, salicylates, succinates, sulfonamides,tartrates salt; organic cationic salts, such as quaternary ammoniumsalts, in particular trimethyl tetradecyl ammonium bromide orbenzethonium chloride; cationic polymers, such as chitosan and(meth)acrylic copolymers (for instance, Eudragit® RS, RL ou E);polyamino acid, proteins or peptides; and mixtures thereof.
 10. Thedosage form according to any one of claims 1 to 7, wherein the quenchingagent is a salt of an anionic exchange resin, the cation of which beingH⁺, a metallic cation and/or NH₄ ⁺.
 11. The dosage form according to anyone of the preceding claims, wherein the quenching agent is a salt of anion exchange resin.
 12. The dosage form according to any one of thepreceding claims, wherein the quenching agent is selected from the groupconsisting of: anionic organic salts, such as sodium dodecyl sulfate orsodium docusate; cationic organic salts, such as quaternary ammoniumsalts, in particular trimethyl tetradecyl ammonium bromide orbenzethonium chloride; strong acid cation exchange resins, of strongalcali anion exchange resins, depending on the AP polarity.
 13. Thedosage form according to claim 11 or 12, wherein said ion exchange resinis a strong acid cation exchange resin where the AP is cationic, or astrong alcali anion exchange resin where the AP is anionic.
 14. Thedosage form according to any one of claims 1I to 13, wherein said resinis derived from a sulphonated styrene-divinylbenzene copolymer.
 15. Thedosage form according to any one of claims 11 to 13, wherein said resinis derived from a styrene-divinylbenzene copolymer bearing quaternaryammonium moieties, or salts thereof.
 16. The dosage form according toany one of the preceding claims, wherein it comprises modified releaseunits of said analgesic active principle and of said quenching agent.17. The dosage form according to claim 16, wherein said modified releaseunits comprise microparticles selected from the group comprising:sustained release microparticles, delayed release microparticles, pulsedrelease microparticles, and mixtures thereof.
 18. The dosage formaccording to any one of the preceding claims, wherein said dosage formis a multimicroparticulate dosage form.
 19. The dosage form according toany one of the preceding claims, wherein said dosage form is amonolithic dosage form.
 20. The dosage form according to any one of thepreceding claims, comprising microparticles of analgesic activeprinciple and microparticles of quenching agent, said microparticleshaving the same size distribution, the same density and being notsievable.
 21. The dosage form according to claim 1, comprising a furtherantimisuse agent.
 22. The dosage form according to the preceding claim,wherein said further antimisuse agent comprises an anti-crushing agent.23. The dosage form according to claims 21 or 22, wherein said furtherantimisuse agent comprises a viscosity agent.
 24. The dosage formaccording to any one of the preceding claims, wherein the antimisuseagent is located: in microparticles containing said antimisuse agent,and/or in a matrix containing said analgesic active principle, and/or ina coating of microparticles containing said analgesic active principle,and/or in a partial or total overcoating of said dosage form, and/orfree from said dosage form.
 25. The dosage form according to claim 22,wherein said anti-crushing agent comprises: a protective overcoating onsaid microparticles, said overcoating having at least one of thefollowing features: viscoelastic properties, to absorb the energydissipated during crushing; a low cohesivity, to favour breaking of theovercoating rather than breaking of the microparticles during crushing;a low surface energy, to favour gliding of the microparticles one on theother during crushing; an ability to form a paste under high shear,and/or free additives, i.e. additives that are not contained in norborne over microparticles, said additives being suitable to impair, oreven to prevent completely, the crushing of the pharmaceutical dosageform containing said analgesic active principle.
 26. The dosage formaccording to claim 25, wherein said overcoating comprises: (i) at leastone film forming polymer insuring the cohesion of the overcoating; andat least one of the following compounds: (ii) a lubricant/lump agent(iii) a viscoelastic compound (iv) a plasticizer.
 27. The dosage formaccording to claim 26, wherein said film-forming polymer (i) is selectedfrom the group comprising cellulose derivatives, acrylic polymers andmixtures thereof.
 28. The dosage form according to claim 26, whereinsaid lubricant/lump agent (ii) is selected from the group comprising:stearic acid, stearates, preferably calcium stearate, zinc stearate ormagnesium stearate, magnesium oxide, poloxamers, sodium benzoate,anionic, cationic or non-ionic surfactants, starch, preferably cornstarch, talc, colloïdal silica, waxes, preferably hydrogenated vegetableoils, and more preferably: cotton hydrogenated oils, soybeanhydrogenated oils, palm hydrogenated oils, glycerol behenate, castorhydrogenated oils, tristearines, tripalmitines, trimyristines, yellowwax, white wax, hard fat, dairy anhydrous fat, lanolins, glycerolpalmitostearate, glycerol stearates, lauric acid macrogolglycerids,cetyl alcohols, polyglycryle di-isostearate, diethylene glycolmonostearate, ethylene monostearate, omega-3 fatty acids, and mixturesthereof, suppository fatty base, comprising glycerine, triglycerids,theobroma oils, cocoa butter, and mixtures thereof, mixtures thereof.29. The dosage form according to claim 26, wherein said viscoeslasticcompound (iii) is selected from the group comprising:poly-N-vinylamides, gums, fatty alcohols, poly-N-vinyl-lactams,polyvinyl alcohols, polyoxiethylenes, polyethylene glycols,polydextroses, hydrogenated mono-, di- and polysaccharides,polyvinylpyrrolidones, these being preferred, and mixtures thereof. 30.The dosage form according to claim 26, wherein said plasticizer (iv) isselected from the group comprising: glycerol, glycerol esters,preferably acetylated glycerides, glycerylmonostearates,glyceryltriacetate, glyceryltributyrate, phtalates, preferably:dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate,citrates, preferably: acetyltributylcitrate, acetyltriethylcitrate,tributylcitrate, triethylcitrate, sebaçates, preferably:diethylsebaçate, dibutylsebaçate, adipates, azelates, benzoates,vegetable oils, preferably: cotton oils, soybean oils, palm oils, castoroils, and mixtures thereof, fumarates, preferably: diethylfumarate,malates, preferably: diethylmalate, oxalates, preferably:diethyloxalate, succinates; preferably: dibutylsuccinate, butyrates,cetyl alcohol esters, triacetine, malonates, preferably:diethylmalonate, and mixtures thereof.
 31. The dosage form according toclaim 25, wherein said additive is selected from the group comprising:compression agents, and/or inert microbeads, and/or gums, and/orviscoelastic compound as defined in claim
 29. 32. The dosage formaccording to claim 23, further comprising viscosity agents which aresuitable to increase the viscosity of a liquid extract prepared fromsaid dosage form, so as to impair misuse of said dosage form.
 33. Thedosage form according to claim 32, wherein said viscosity agent isselected from the group comprising: acrylic polyacids and derivativesthereof, and/or polyoxyethylenes, and/or polyvinyl alcohol, and/orpolyvinylpyrrolidones, and/or gelatins cellulose derivatives, forinstance hydroxypropylmethylcellulose, methylcellulose,hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose,and/or polysaccharides, preferably from the group comprising sodiumalginate, pectins, guar, xanthanes, carraghenanes, gellanes, and/ormixtures thereof.
 34. The dosage form according to claim 1, wherein saiddosage form comprises a plurality of microparticles for the modifiedrelease of said analgesic active principle, each microparticlesindividually comprising a core and a coating on said core, wherein thecore comprises at least one analgesic active principle and wherein thecoating controls the modified release of said active principle, saidmicroparticles having a mean diameter lower than or equal to 1,000 μm.35. The dosage form according to any one of the preceding claims,wherein said analgesic active principle comprises an opioid activeprinciple in the form of a salt.
 36. The dosage form according to claim35, wherein said opioid active principle is selected from the groupcomprising: anileridine, acetorphine, acetylalphamethylfentanyl,acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine,alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol,alphamethylfentanyl, alpha-methylthiofentanyl, alphaprodine,anileridine, atropine, butorphanol, benzethidine, benzylmorphine,beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol,betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine,butyrate de dioxaphetyl, clonitazene, cyclazocine, cannabis,cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine,dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine,dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene,difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate,dipipanone, drotebanol, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,etoxeridine, fentanyl, furethidine, heroine, hydrocodone,hydromorphinol, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphane, lofentanil, levomethorphane, levomoramide,levophenacylmorphane, levorphanol, meptazinol, meperidine, metazocine,methadone, methyldesorphine, methyldihydro-morphine, methylphenidate,methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide,morpheridine, morphine, mppp, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine,norlevorphanol, normethadone, normorphine, norpipanone, opium,oxycodone, oxymorphone, papavereturn, phenadoxone, phenoperidine,promedol, properidine, propiram, propoxyphene para-fluorofentanyl,pepap, pentazocine, pethidine, phenampromide, phenazocine,phenomorphane, phenoperidine, pholcodine, piminodine, piritramide,proheptazine, propanolol, properidine, propiram, racemethorphane,racemoramide, racemorphane, remifentanil, sufentanil, thebacone,thebaine, thiofentanyl, tilidine, trimeperidine, tramodol,pharmacologically acceptable salts thereof and their mixtures.
 37. Thedosage form according to any one of the preceding claims, comprising atleast one non-analgesic active principle selected from the groupcomprising: anti-depressants, amphetamines, anorectics, pain killers,antiepileptics, anitmigraines, antiparkinson agents, antitussives,anxiolytics, barbiturics, benzodiazepines, hypnotics, laxatives,neuroleptics, psychostimulants, psychotropes, sedatives, stimulants,anti-inflammatory agents, the pharmacologically acceptable saltsthereof, and their mixtures.
 38. The dosage form according to claim 1,which is in the form of tablets, powders, sachets, or capsules.